Transgenic Marmosets
Introduction Transgenic marmosets are genetically modified primates with the potential to mimic human genetic conditions more closely than current models, most notably Mus musculus ''(1). Background Neuroscientists have been seeking transgenic monkeys for research purposes for some time. Certain neurological disorders such as autism, schizophrenia, and Alzheimer's disease cannot be properly studied in mice due to limitations of the mouse nervous system. Researchers have persevered with mice because there is a targeted gene-editing strategy proved to be effective in manipulating the genes of the animals. More specifically, the strategy relies on rare, spontaneous DNA-swapping mutations that alter or disable certain genes. The method requires a great deal of work on the part of researchers, who must design the desired mutation and introduce it into embryonic stem cells. Once the mutation has been introduced, the researchers then must detect the mutant embryonic cells and integrate those cells into an already-developing mouse embryo. From this point onwards the scientists can only hope that when the patchwork animal develops fully it will carry the specific mutation introduced into its embryo. This approach relies on the fact that mouse embryos are relatively cheap and easy to reproduce in large numbers. Evidence of the need for a more advanced nervous system lies in the fact that many neuroactive drugs that have shown promise in early trials have proven to be ineffective in human trials. New technologies surrounding transgenic marmosets are exciting because it is now possible for the first time to try out some treatments for genetic-based diseases in primates on primates. Methods The first transgenic marmoset was developed by Erika Sasaki and her colleagues at the Central Institute for Experimental Animals in Japan in 2009. By adding retrovirus vectors to a soup of sugary solution and injecting said solution into embryos of marmosets, researchers succeeded in introducing the GFP gene into the monkeys. While this technique has been successful, it has its limitations, notably the size of genes that can be carried by the retroviruses used in the method (4). Another gene-editing technique employs the use of zinc-finger nucleases to hone in on specific genomic regions, cut genes to open and disrupt their function, and allow researchers to substitute in external DNA one monkey embryo at a time (2). A third method used in the genetic manipulation of non-human primates is the CRISPR method. CRISPR employs the use of specifically engineered RNA to target the gene of interest and cut it, disabling it and making it vulnerable to strategic insertions of small amounts of engineered DNA. Feng Zhang, a systematic biologist at Massachusetts Institute of Technology, demonstrated in May that this technique can be utilized to make not one but multiple specific genetic alterations in mouse embryos (3). Currently, MIT researchers are working closely with collaborators at the Oregon National Primate Research Center in Beaverton to use the CRISPR method to disable genes in fertilized monkey eggs. One particular gene that has been implicated in some human cases of autism, SHANK3, is presently being targeted for disruption by Mr. Zhang's lab. The lab hopes that one day CRISPR may be used to label monkey neuron types or control them with light, as is currently done with mouse neurons. One day this may allow for the more in-depth study in many important areas of neuroscience - cognition, attention, memory, and decision making. Animal research is the subject of a great deal of controversies. While scientists argue that transgenic monkeys like the tranasgenic marmoset may be the best way to search for treatments for brain diseases and the investigation of how nerual networks generate consciousness. “You want to match the model system to the question you’re asking,” says Anthony Movshon, a monkey-vision researcher at New York University. "It's just as unethical to use a mouse for an experiment for which its not suited." (1) References 1. Shen, H. (2013). Precision gene editing paves way for transgenic monkeys.''Nature, 503, 14-15. 2. Yang, S. H., Cheng, P. H., Banta, H., Piotrowska-Nitsche, K., Yang, J. J., Cheng, E. C., ... & Chan, A. W. (2008). Towards a transgenic model of Huntington’s disease in a non-human primate. Nature, 453(7197), 921-924. 3. Wang, H., Yang, H., Shivalila, C. S., Dawlaty, M. M., Cheng, A. W., Zhang, F., & Jaenisch, R. (2013). One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell, 153(4), 910-918. 4. Sasaki, E., Suemizu, H., Shimada, A., Hanazawa, K., Oiwa, R., Kamioka, M., ... & Nomura, T. (2009). Generation of transgenic non-human primates with germline transmission. Nature, 459(7246), 523-527.